Chronic kidney disease (CKD) is a disease that affects 13.3 million Japanese, corresponding to roughly 13% of the Japanese adult population, and threatens the health of Japanese citizens due to the risk of progressing to end stage kidney disease (ESKD). Chronic kidney disease includes all pathological states in which depressed renal function as represented by glomerular filtration rate is found, or findings suggesting kidney damage persist in a chronic state (three months or longer). There is no effective treatment method for chronic kidney disease, and if chronic kidney disease progresses resulting in further depression of renal function, there is the risk of uremia, resulting in the need for artificial dialysis or kidney transplant, which will place a considerable burden on the patient in terms of health care costs (Non-Patent Document 1). Chronic kidney disease does not exhibit subjective symptoms. Diagnosis using markers for early diagnosis of renal failure is necessary for early diagnosis of chronic kidney disease and inhibition of its progression. However, there is currently no biomarker that is satisfactory in terms of accurately reflecting the progression of renal dysfunction at an earlier stage than the occurrence of changes in renal function as represented by glomerular filtration rate.
An experimental animal model of acute kidney injury (AKI) is able to reproduce the early stages of renal dysfunction. Acute kidney injury is a disease in which renal function decreases rapidly over several weeks or several days. A known model of this disease is an acute kidney injury experimental model which is induced by a surgical procedure or administration of a drug. The “gold standards” for diagnosing acute kidney injury are urine production volume and serum creatinine concentration. Serum creatinine concentration is superior in that it can be evaluated without performing a biopsy regardless of the presence or absence of urination. However, glomerular filtration rate is required to be in a steady state. In a experimental animal model of acute kidney injury, which is not sensitive to small fluctuations in glomerular filtration rate, changes in glomerular filtration rate become apparent at a comparatively late stage. Since serum creatinine concentration also fluctuates due to conditions such as age, gender, muscle mass or medications being taken at the time, it cannot be a specific marker (Non-Patent Document 2). Reported examples of markers for acute kidney injury include neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), proteins such as fatty acid binding proteins or cystatin C, and metabolic low molecular weight compounds such as homovanillic acid sulfate or trimethylamine-N-oxide. However, none of these markers are detected in the early stage of renal failure.
Since concentrations of D-serine and D-alanine in the serum of renal failure patients are higher than serum concentrations in normal individuals, and both the D-form concentrations and ratio of D-form concentration/(D-form concentration+L-form concentration) correlate with creatinine, these amino acids have been suggested to be candidates for markers of renal proximal tubular dysfunction (Non-Patent Document 3). It is also disclosed that D-amino acids (Ala, Pro, Ser) in the serum of nephritis patients tend to be elevated and have a correlation with creatinine level (Non-Patent Document 9). In addition, D-alanine, D-serine, D-glutamic acid and D-aspartic acid are observed in the serum of renal failure patients, and because of this, measurement of serum D-alanine concentration has been suggested to be useful in the diagnosis of renal failure (Non-Patent Document 5). D-serine and D-alanine concentration in the urine along with the ratio of the D-form to the total of the D-form and L-form were investigated in healthy individuals of various age groups, and it was suggested that processing of D-serine in the kidneys is different (Non-Patent Document 6). Although one or more amino acids selected from the group consisting of D-serine, D-threonine, D-alanine, D-asparagine, D-allo-threonine, D-glutamine, D-proline and D-phenylalanine were disclosed as being able to be used as pathological indicators of kidney disease (Patent Document 1). However, even though it is described in this document that a body fluid such as blood, plasma or urine is used as a specimen, blood is the only specimen used to determine pathological indicators for kidney disease in the examples, while there is nothing disclosed as to whether or not amino acids present in urine can be used as pathological indicators of kidney disease. It is also disclosed that the D-form ratios of alanine, valine, proline, threonine, aspartic acid and asparagine increase significantly in the urine of renal failure patients, while there is no significant differences with respect to methionine and serine (Non-Patent Document 7). However, in this document, although the ratio of the D-form concentration/(D-form concentration+L-form concentration) of each amino acid is calculated in renal failure patients for which pathological assessment criteria have not been indicated, increases in these ratios are merely indicated randomly (or vaguely) irrespective of disease stage, and there are no descriptions or suggestions as to the fact that fluctuations in these ratios correlate with pathological or other biomarkers of renal failure. After the priority date of the present application, urinary D/L-serine ratio was suggested to be able to be used as a biomarker capable of detecting early stage ischemic renal failure and classifying pathological stage since it decreases over time following ischemia reperfusion injury (Non-Patent Document 8). D-amino acid oxidase, which is involved in the decomposition of D-amino acids, is expressed in renal proximal tubules, and the enzyme activity of D-amino acid oxidase is known to decrease in ischemia reperfusion model rats (Non-Patent Document 4). L-serine is reabsorbed while D-serine is hardly reabsorbed at all under physiological conditions. However, the manner in which D-serine and other D-amino acids fluctuate in the early stage of renal failure is unknown.